Mammalian cardiac development requires continuous proliferation of cardiomyocytes throughout gestation (1, 2). During the perinatal period, cardiomyocyte proliferation rapidly declines, and the majority of cardiomyocytes undergo cell cycle arrest with terminal differentiation (3, 4). Postnatal arrest of the cardiomyocyte cell cycle is a key event for maturation of the mammalian heart, but this process is poorly understood (3).
Mitogenic cardiomyopathy is a very rare form of pediatric cardiomyopathy characterized by persistent markers of mitotic activity at high levels in cardiomyocytes (5). Among five previously reported infants with this condition, there were two pairs of siblings, one of whom had parental consanguinity supporting a recessive genetic disorder. Recently, persistent postnatal cardiomyocyte division was demonstrated in mice lacking the transcription factor Meis (16). However, no naturally inherited conditions associated with delayed postnatal cardiomyocyte cell cycle arrest have previously been characterized in humans. Recognition and characterization of such a disorder has the potential to identify important regulators of the transition of cardiomyocytes from active proliferation to terminal differentiation.
In this study, we identify ALMS1 mutations in 2 siblings and 4 previously reported infants with mitogenic cardiomyopathy. We show that knockdown of murine Alms1 increases cell cycle progression in cultured neonatal murine cardiomyocytes. Likewise, Alms1 knockdown increases the number of induced cardiomyocytes in cultured cells. At postnatal day 15 (1 week beyond the normal murine window of postnatal cardiomyocyte cell cycle arrest), ALMS1-deficient mice show persistent cardiomyocyte proliferation, indicating that ALMS1-deficient cardiomyocytes may have an impaired terminal differentiation of cardiomyocytes.